{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T03:33:35Z","timestamp":1775273615613,"version":"3.50.1"},"reference-count":99,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T00:00:00Z","timestamp":1690502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"La Caixa Foundation","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}]},{"name":"La Caixa Foundation","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}]},{"name":"La Caixa Foundation","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}]},{"name":"La Caixa Foundation","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}]},{"name":"La Caixa Foundation","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"name":"La Caixa Foundation","award":["2021.06954.BD"],"award-info":[{"award-number":["2021.06954.BD"]}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014717","name":"Centro 2020","doi-asserted-by":"publisher","award":["2021.06954.BD"],"award-info":[{"award-number":["2021.06954.BD"]}],"id":[{"id":"10.13039\/501100014717","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FCT","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}]},{"name":"FCT","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}]},{"name":"FCT","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}]},{"name":"FCT","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}]},{"name":"FCT","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"name":"FCT","award":["2021.06954.BD"],"award-info":[{"award-number":["2021.06954.BD"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The intracerebroventricular (icv) injection of amyloid peptides (A\u03b2) models Alzheimer\u2019s disease (AD) in mice, as typified by the onset within 15 days of deficits of memory and of hippocampal long-term potentiation (LTP) that are prevented by the blockade of adenosine A2A receptors (A2AR). Since A2AR overfunction is sufficient to trigger memory deficits, we tested if A2AR were upregulated in hippocampal synapses before the onset of memory deficits to support the hypothesis that A2AR overfunction could be a trigger of AD. Six to eight days after A\u03b2-icv injection, mice displayed no alterations of hippocampal dependent memory; however, they presented an increased excitability of hippocampal synapses, a slight increase in LTP magnitude in Schaffer fiber-CA1 pyramid synapses and an increased density of A2AR in hippocampal synapses. A2AR blockade with SCH58261 (50 nM) normalized excitability and LTP in hippocampal slices from mice sacrificed 7\u20138 days after A\u03b2-icv injection. Fifteen days after A\u03b2-icv injection, mice displayed evident deficits of hippocampal-dependent memory deterioration, with reduced hippocampal CA1 LTP but no hyperexcitability and a sustained increase in synaptic A2AR, which blockade restored LTP magnitude. This shows that the upregulation of synaptic A2AR precedes the onset of deterioration of memory and of hippocampal synaptic plasticity, supporting the hypothesis that the overfunction of synaptic A2AR could be a trigger of memory deterioration in AD.<\/jats:p>","DOI":"10.3390\/biom13081173","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T01:51:47Z","timestamp":1690509107000},"page":"1173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Adenosine A2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to A\u03b21\u201342 to Model Early Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"C\u00e1tia R.","family":"Lopes","sequence":"first","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8017-104X","authenticated-orcid":false,"given":"Ant\u00f3nio C.","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-3411","authenticated-orcid":false,"given":"Henrique B.","family":"Silva","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Paula M.","family":"Canas","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Paula","family":"Agostinho","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-6422","authenticated-orcid":false,"given":"Rodrigo A.","family":"Cunha","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5122-1802","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Lopes","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/B978-0-12-819410-2.00022-9","article-title":"Synaptic dysfunction in early phases of Alzheimer\u2019s disease","volume":"184","author":"Pelucchi","year":"2022","journal-title":"Handb. Clin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1129036","DOI":"10.3389\/fnsyn.2023.1129036","article-title":"Alzheimer\u2019s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression","volume":"15","author":"Meftah","year":"2023","journal-title":"Front. Synaptic. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1111\/j.1471-4159.2006.03935.x","article-title":"Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer\u2019s disease","volume":"98","author":"Kirvell","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuropharm.2013.08.026","article-title":"Predominant loss of glutamatergic terminal markers in a \u03b2-amyloid peptide model of Alzheimer\u2019s disease","volume":"76","author":"Canas","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40478-019-0670-1","article-title":"Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer\u2019s disease","volume":"7","author":"Sri","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1038\/ncomms11915","article-title":"Early synaptic deficits in the APP\/PS1 mouse model of Alzheimer\u2019s disease involve neuronal adenosine A2A receptors","volume":"7","author":"Haberl","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.neurobiolaging.2005.09.012","article-title":"Hippocampal synaptic loss in early Alzheimer\u2019s disease and mild cognitive impairment","volume":"27","author":"Scheff","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.trci.2019.11.002","article-title":"Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer\u2019s disease","volume":"5","author":"Galasko","year":"2019","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1177\/0271678X231153730","article-title":"In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer\u2019s disease","volume":"43","author":"Zhang","year":"2023","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1152\/jn.00620.2014","article-title":"Localized adenosine signaling provides fine-tuned negative feedback over a wide dynamic range of neocortical network activities","volume":"113","author":"Wall","year":"2015","journal-title":"J. Neurophysiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lopes, C.R., Gon\u00e7alves, F.Q., Olaio, S., Tom\u00e9, A.R., Cunha, R.A., and Lopes, J.P. (2023). Adenosine A2A receptors shut down adenosine A1 receptor-mediated presynaptic inhibition to promote implementation of hippocampal long-term potentiation. Biomolecules, 13.","DOI":"10.3390\/biom13040715"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1111\/jnc.13724","article-title":"How does adenosine control neuronal dysfunction and neurodegeneration?","volume":"139","author":"Cunha","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/0306-4522(87)90043-1","article-title":"Synaptic and extrasynaptic localization of adenosine binding sites in the rat hippocampus","volume":"21","author":"Tetzlaff","year":"1987","journal-title":"Neuroscience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0006-8993(03)03247-5","article-title":"Subcellular localization of adenosine A1 receptors in nerve terminals and synapses of the rat hippocampus","volume":"987","author":"Rebola","year":"2003","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.neuroscience.2005.01.014","article-title":"Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat","volume":"132","author":"Rebola","year":"2005","journal-title":"Neuroscience"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0306-4522(02)00080-5","article-title":"Adenosine A2A receptor facilitation of hippocampal synaptic transmission is dependent on tonic A1 receptor inhibition","volume":"112","author":"Lopes","year":"2002","journal-title":"Neuroscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1007\/s12035-016-9774-9","article-title":"Caffeine reverts memory but not mood impairment in a depression-prone mouse strain with up-regulated adenosine A2A receptor in hippocampal glutamate synapses","volume":"54","author":"Machado","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.neuron.2007.11.023","article-title":"Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses","volume":"57","author":"Rebola","year":"2008","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4386","DOI":"10.1111\/bph.14497","article-title":"Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons","volume":"175","author":"Mouro","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1038\/s41380-018-0110-9","article-title":"Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors","volume":"25","author":"Ferreira","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1460-9568.2011.07719.x","article-title":"Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing","volume":"34","author":"Costenla","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7833","DOI":"10.1073\/pnas.1423088112","article-title":"Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress","volume":"112","author":"Kaster","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14741","DOI":"10.1523\/JNEUROSCI.3728-09.2009","article-title":"Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by \u03b2-amyloid peptides via p38 mitogen-activated protein kinase pathway","volume":"29","author":"Canas","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"ENEURO.0385-18.2018","DOI":"10.1523\/ENEURO.0385-18.2018","article-title":"Neuronal adenosine A2A receptors are critical mediators of neurodegeneration triggered by convulsions","volume":"5","author":"Canas","year":"2018","journal-title":"eNeuro"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1111\/bph.13180","article-title":"Adenosine A2A receptors are necessary and sufficient to trigger memory impairment in adult mice","volume":"172","author":"Pagnussat","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1038\/mp.2014.182","article-title":"Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory","volume":"20","author":"Li","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3636","DOI":"10.1093\/brain\/awz288","article-title":"Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor","volume":"142","author":"Carvalho","year":"2019","journal-title":"Brain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.pneurobio.2007.09.002","article-title":"Adenosine A2A receptors and brain injury: Broad spectrum of neuroprotection, multifaceted actions and \u201cfine tuning\u201d modulation","volume":"83","author":"Chen","year":"2007","journal-title":"Prog. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.2174\/0929867328666211129122550","article-title":"A2A adenosine receptor antagonists in neurodegenerative diseases","volume":"29","author":"Merighi","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/mp.2014.151","article-title":"A2A adenosine receptor deletion is protective in a mouse model of Tauopathy","volume":"21","author":"Laurent","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.nbd.2018.05.024","article-title":"Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer\u2019s disease","volume":"117","author":"Silva","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.nbd.2017.10.014","article-title":"Istradefylline reduces memory deficits in aging mice with amyloid pathology","volume":"110","author":"Orr","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.bcp.2019.06.008","article-title":"The physiological effects of caffeine on synaptic transmission and plasticity in the mouse hippocampus selectively depend on adenosine A1 and A2A receptors","volume":"166","author":"Lopes","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3233\/JAD-2009-0920","article-title":"Midlife coffee and tea drinking and the risk of late-life dementia: A population-based CAIDE study","volume":"16","author":"Eskelinen","year":"2009","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"607","DOI":"10.3233\/JAD-2010-101428","article-title":"Coffee intake in midlife and risk of dementia and its neuropathologic correlates","volume":"23","author":"Gelber","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Dong, X., Li, S., Sun, J., Li, Y., and Zhang, D. (2020). Association of coffee, decaffeinated coffee and caffeine intake from coffee with cognitive performance in older adults: National Health and Nutrition Examination Survey (NHANES) 2011\u20132014. Nutrients, 12.","DOI":"10.3390\/nu12030840"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.neurobiolaging.2017.08.010","article-title":"Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer\u2019s disease","volume":"60","author":"Nho","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Siokas, V., Mouliou, D.S., Liampas, I., Aloizou, A.-M., Folia, V., Zoupa, E., Papadimitriou, A., Lavdas, E., Bogdanos, D.P., and Dardiotis, E. (2022). Analysis of ADORA2A rs5760423 and CYP1A2 rs762551 genetic variants in patients with Alzheimer\u2019s disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214400"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"104570","DOI":"10.1016\/j.nbd.2019.104570","article-title":"Synaptic and memory dysfunction in a \u03b2-amyloid model of early Alzheimer\u2019s disease depends on increased formation of ATP-derived extracellular adenosine","volume":"132","author":"Lopes","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"105441","DOI":"10.1016\/j.nbd.2021.105441","article-title":"Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction","volume":"157","author":"Augusto","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sim\u00f5es, A.P., Gon\u00e7alves, F.Q., Rial, D., Ferreira, S.G., Lopes, J.P., Canas, P.M., and Cunha, R.A. (2022). CD73-mediated formation of extracellular adenosine is responsible for adenosine A2A receptor-mediated control of fear memory and amygdala plasticity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112826"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1021\/acschemneuro.2c00810","article-title":"Increased synaptic ATP release and CD73-mediated formation of extracellular adenosine in the control of behavioral and electrophysiological modifications caused by chronic stress","volume":"14","author":"Dias","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1007\/s12035-022-03162-1","article-title":"Increased ATP release and higher impact of adenosine A2A receptors on corticostriatal plasticity in a rat model of presymptomatic Parkinson\u2019s disease","volume":"60","author":"Matheus","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Gessi, S., Poloni, T.E., Negro, G., Varani, K., Pasquini, S., Vincenzi, F., Borea, P.A., and Merighi, S. (2021). A2A adenosine receptor as a potential biomarker and a possible therapeutic target in Alzheimer\u2019s disease. Cells, 10.","DOI":"10.3390\/cells10092344"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.neuroscience.2008.06.036","article-title":"Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1\u201342: Involvement of endoplasmic reticulum calcium release in oligomer-induced cell death","volume":"155","author":"Resende","year":"2008","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"ref_49","first-page":"53308","article-title":"Intracerebroventricular injection of amyloid-\u03b2 peptides in normal mice to acutely induce Alzheimer-like cognitive deficits","volume":"109","author":"Kim","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jneumeth.2006.12.018","article-title":"Capabilities of the WinLTP data acquisition program extending beyond basic LTP experimental functions","volume":"162","author":"Anderson","year":"2007","journal-title":"J. Neurosci. Methods"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1038\/sj.bjp.0705692","article-title":"Binding of the prototypical adenosine A2A receptor agonist CGS 21680 to the cerebral cortex of adenosine A1 and A2A receptor knockout mice","volume":"141","author":"Lopes","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.expneurol.2007.11.013","article-title":"Adenosine A2A receptor blockade prevents memory dysfunction caused by \u03b2-amyloid peptides but not by scopolamine or MK-801","volume":"210","author":"Cunha","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1111\/jnc.15575","article-title":"Impact of blunting astrocyte activity on hippocampal synaptic plasticity in a mouse model of early Alzheimer\u2019s disease based on amyloid-\u03b2 peptide exposure","volume":"160","author":"Lopes","year":"2022","journal-title":"J. Neurochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nrn.2016.141","article-title":"Network abnormalities and interneuron dysfunction in Alzheimer disease","volume":"17","author":"Palop","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41398-022-02024-7","article-title":"Neuronal hyperexcitability in Alzheimer\u2019s disease: What are the drivers behind this aberrant phenotype?","volume":"12","author":"Matosin","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"101865","DOI":"10.1016\/j.arr.2023.101865","article-title":"The hippocampus associated GABAergic neural network impairment in early-stage of Alzheimer\u2019s disease","volume":"86","author":"Tang","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1001\/jamaneurol.2013.136","article-title":"Seizures and epileptiform activity in the early stages of Alzheimer disease","volume":"70","author":"Vossel","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1093\/brain\/awab442","article-title":"Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer\u2019s disease","volume":"145","author":"Ranasinghe","year":"2022","journal-title":"Brain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1002\/ana.24794","article-title":"Incidence and impact of subclinical epileptiform activity in Alzheimer\u2019s disease","volume":"80","author":"Vossel","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neuron.2007.07.025","article-title":"Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer\u2019s disease","volume":"55","author":"Palop","year":"2007","journal-title":"Neuron"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"951","DOI":"10.3233\/JAD-200527","article-title":"Reduction of dendritic inhibition in CA1 pyramidal neurons in amyloidosis models of early Alzheimer\u2019s disease","volume":"78","author":"Ruiter","year":"2020","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13195-021-00859-8","article-title":"Reversible GABAergic dysfunction involved in hippocampal hyperactivity predicts early-stage Alzheimer disease in a mouse model","volume":"13","author":"Li","year":"2021","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1186\/s12967-023-04078-7","article-title":"Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer\u2019s mouse model","volume":"21","author":"Wander","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/j.neurobiolaging.2005.09.022","article-title":"Early neuropathology of somatostatin\/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer\u2019s disease","volume":"27","author":"Ramos","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/nm.3639","article-title":"GABA from reactive astrocytes impairs memory in mouse models of Alzheimer\u2019s disease","volume":"20","author":"Jo","year":"2014","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1001\/jamaneurol.2021.3310","article-title":"Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity: A randomized clinical trial","volume":"78","author":"Vossel","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/hipo.22392","article-title":"Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus","volume":"25","author":"Rombo","year":"2015","journal-title":"Hippocampus"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1016\/S0028-3908(99)00237-3","article-title":"Purinergic modulation of [3H]GABA release from rat hippocampal nerve terminals","volume":"39","author":"Cunha","year":"2000","journal-title":"Neuropharmacology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s11064-005-2682-4","article-title":"GABA release modified by adenosine receptors in mouse hippocampal slices under normal and ischemic conditions","volume":"30","author":"Saransaari","year":"2005","journal-title":"Neurochem. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"eabk2055","DOI":"10.1126\/science.abk2055","article-title":"Convergence of adenosine and GABA signaling for synapse stabilization during development","volume":"374","author":"Zappettini","year":"2021","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"18492","DOI":"10.1523\/JNEUROSCI.1828-13.2013","article-title":"Antagonistic interaction between adenosine A2A receptors and Na+\/K+-ATPase-\u03b12 controlling glutamate uptake in astrocytes","volume":"33","author":"Matos","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nn.3930","article-title":"Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory","volume":"18","author":"Orr","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s11302-016-9535-2","article-title":"Adenosine A2A receptor and ecto-5\u2019-nucleotidase\/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)","volume":"12","author":"Ferreirinha","year":"2016","journal-title":"Purinergic Signal."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s11302-013-9364-5","article-title":"A1R-A2AR heteromers coupled to Gs and Gi\/0 proteins modulate GABA transport into astrocytes","volume":"9","author":"Navarro","year":"2013","journal-title":"Purinergic Signal."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.biopsych.2015.02.026","article-title":"Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: Relevance to schizophrenia","volume":"78","author":"Matos","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1002\/glia.24384","article-title":"Astrocytic A2A receptors silencing negatively impacts hippocampal synaptic plasticity and memory of adult mice","volume":"71","author":"Madeira","year":"2023","journal-title":"Glia"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuroscience.2015.03.006","article-title":"Hippocampal plasticity during the progression of Alzheimer\u2019s disease","volume":"309","author":"Mufson","year":"2015","journal-title":"Neuroscience"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.3233\/JAD-160845","article-title":"Synaptic compensation as a probable cause of prolonged mild cognitive impairment in Alzheimer\u2019s disease: Implications from a transgenic mouse model of the disease","volume":"56","author":"Baazaoui","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_79","first-page":"718","article-title":"Adenosine A2A receptors modulate \u03b1-synuclein aggregation and toxicity","volume":"27","author":"Ferreira","year":"2017","journal-title":"Cereb. Cortex"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"108106","DOI":"10.1016\/j.neuropharm.2020.108106","article-title":"Hippocampal synaptic dysfunction in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis: Reversal by adenosine A2AR blockade","volume":"171","author":"Rei","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"105137","DOI":"10.1016\/j.nbd.2020.105137","article-title":"Adenosine A2A receptors format long-term depression and memory strategies in a mouse model of Angelman syndrome","volume":"146","author":"Lopes","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41398-021-01238-5","article-title":"Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice","volume":"11","author":"Ferrante","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"113929","DOI":"10.1016\/j.expneurol.2021.113929","article-title":"Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice","volume":"350","author":"Li","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/hipo.20894","article-title":"Enhancement of AMPA currents and GluR1 membrane expression through PKA-coupled adenosine A2A receptors","volume":"22","author":"Dias","year":"2012","journal-title":"Hippocampus"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1111\/jnc.13291","article-title":"Adenosine A\u2082A receptors permit mGluR5-evoked tyrosine phosphorylation of NR2B (Tyr1472) in rat hippocampus: A possible key mechanism in NMDA receptor modulation","volume":"135","author":"Sarantis","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Franco, R., Rivas-Santisteban, R., Casanovas, M., Lillo, A., Saura, C.A., and Navarro, G. (2020). Adenosine A2A receptor antagonists affects NMDA glutamate receptor function. Potential to address neurodegeneration in Alzheimer\u2019s disease. Cells, 9.","DOI":"10.3390\/cells9051075"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/nn.2341","article-title":"Adenosine A2A receptor mediates microglial process retraction","volume":"12","author":"Orr","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1742-2094-10-16","article-title":"Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia","volume":"10","author":"Gomes","year":"2013","journal-title":"J. Neuroinflammation"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.bbr.2018.02.038","article-title":"Adenosine A2A receptor involves in neuroinflammation-mediated cognitive decline through activating microglia under acute hypobaric hypoxia","volume":"347","author":"Chen","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"136431","DOI":"10.1016\/j.neulet.2021.136431","article-title":"High glutamate concentration reverses the inhibitory effect of microglial adenosine 2A receptor on NLRP3 inflammasome assembly and activation","volume":"769","author":"Du","year":"2022","journal-title":"Neurosci. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1471-4159.2011.07178.x","article-title":"Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction","volume":"117","author":"Rebola","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1093\/brain\/awy351","article-title":"CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling","volume":"142","author":"Meng","year":"2019","journal-title":"Brain"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"639322","DOI":"10.3389\/fncel.2021.639322","article-title":"Crosstalk between ATP-P2X7 and adenosine A2A receptors controlling neuroinflammation in rats subject to repeated restraint stress","volume":"15","author":"Dias","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.1007\/s00018-021-03761-6","article-title":"Structure and function of adenosine receptor heteromers","volume":"78","author":"Franco","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1523\/JNEUROSCI.5255-07.2008","article-title":"A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs","volume":"28","author":"Shen","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Shen, H.-Y., Canas, P.M., Garcia-Sanz, P., Lan, J.-Q., Boison, D., Moratalla, R., Cunha, R.A., and Chen, J.-F. (2013). Adenosine A2A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080902"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.biopsych.2013.05.003","article-title":"Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain","volume":"75","author":"Wei","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"109421","DOI":"10.1016\/j.neuropharm.2023.109421","article-title":"Striatopallidal adenosine A2A receptor modulation of goal-directed behavior: Homeostatic control with cognitive flexibility","volume":"226","author":"Chen","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"702581","DOI":"10.3389\/fnins.2021.702581","article-title":"Adenosine A2A receptors as biomarkers of brain diseases","volume":"15","author":"Canas","year":"2021","journal-title":"Front. Neurosci."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/8\/1173\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:21:09Z","timestamp":1760127669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/8\/1173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,28]]},"references-count":99,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["biom13081173"],"URL":"https:\/\/doi.org\/10.3390\/biom13081173","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,28]]}}}